`These records are from CDER’s historical file of information
`previously disclosed under the Freedom of Information Act (FOIA)
`for this drug approval and are being posted as is. They have not
`been previously posted on Drugs@FDA because of the quality
`(e.g., readability) of some of the records. The documents were
`redacted before amendments to FOIA required that the volume of
`redacted information be identified and/or the FOIA exemption be
`cited. These are the best available copies.
`
`Page 1 of 286
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`•
`
`20613
`28613
`
`Page 2 of 286
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`SLAYBACK EXHIBIT 1031 , of 3
`1 OF 3
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`J06 /S
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`

`NDA 20-613
`
`Alphagan™
`
`(brimonidine tartrate ophthalmic solution) 0.2% Sterile
`
`Allergan
`
`Volume 1 of 1
`
`Joanne Holmes
`phone 7-2527
`e-mail HolmesJ
`
`Page 4 of 286
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`

`NDA 20-613
`
`Allergan, Inc.
`Attention: Adelbert L. Stagg, Ph.D.
`Director, Regulatory Affairs
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92713-9534
`
`Dear Dr. Stagg:
`
`Please refer to your August 31, 1995, new drug application submitted under section SOS(b) of
`the Federal Food, Drug, and Cosmetic Act for Alphagan"' (brimonidine tartrate ophthalmic
`soluti:m) 0.2%.
`
`We acknowledge receipt of your amendments dated October 12 and 23, 1995, and
`February 26, March 1, 18, 22, and 26, AprilS, II, and 25, May 8, 10 (two), 14, 16, June 4,
`12 (two), July 16, and August 28, 1996.
`
`This new drug application provides for the indication of lowering intraocular pressure in
`patients with open-angle glaucoma or ocular hypertension.
`
`We have completed the review of this application, including the submitted draft labeling, and
`have concluded that adequate information has been presented to demonstrate that the drug
`produ~t is safe and effective for use as recommended in the draft labeling in the submission
`dated August 28, 1996 with the following revision: the first sentence of the Clinical
`Pharmacology se:::tion should be revised into the following two sentences, "ALPHAGAN"' is
`an alpha adrenergic receptor agonist. It has a peak ocular hypotensive effect occurring at two
`hours post-dosing." Accordingly, the application is approved effective on the date of this
`letter.
`
`The final printed labeling (fPL) must be identical to the draft labeling submitted on August 28,
`1996, as revised above. Marketing the product witl• FPL that is not identical to this revised
`draft labeling may render the product misbranded and an unapproved new drug.
`
`Please submit sixteen copies of the FPL as soon as it is available, in no case more than 30 days
`after it is printed. Please individually mount ten of the copies on heavy weight paper or
`similar material. For administrative purposes this submission should be designated "FINAL
`PRINTED LABELING" for approved NDA 20-613. Approval of this submission by FDA is
`not required before the labeling is used.
`
`Should additional infonnation relating to the safety and effectiveness of the drug become
`available, additional revisions of that labeling may be required.
`
`Page 5 of 286
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`

`NDA 20-613
`Page 2
`
`In addition, please submit three copies of the introductory promotional material that you
`propose to use for this product. All proposed materials should be submitted in draft or mock(cid:173)
`up form, not final print. Please submit one copy to the Division of Anti-Inflammatory,
`Analgesic and Ophthalmic Drug Prodncts and two copies of both the promotional material and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`Validation of the regulatory methods has not been completed. At the present time, it is the
`policy of the Center not to withhold approval because the methods are being validated.
`Nevertheless, we expect your continued cooperation to resolve any problems that may be
`identified.
`
`In addition, we acknowledge the commitment made during the September 6, 1996, telephone
`conversation between Peter Kresel (Allergan, Inc.) and Wiley Chambers (FDA). Allergan,
`Inc .. agreed to conduct a Phase 4 study to further evaluate the potential (in at least two
`
`Pl~ase submit one market package of the drug when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`If you have any questions, please contact:
`
`Joanne Holmes, M.B.A.
`Project Manager
`(3UJ 1 827-2090
`
`Sincerely yours,
`
`Michael Weintraut, M.D.
`Directt'r
`Offi-e !)f Drug Evaluation V
`Cen.er for Drug Evaluation and Research
`
`Page 6 of 286
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`

`FINAL PRINTED LABELING HAS NOT BEEN SUBMITTED TO THE FDA.
`
`DRAFT LABELING IS NO LONGER BEING SUPPLIED SO AS TO ENSURE
`
`ONLY CORRECT AND CURRENT INFORMATION IS DISSEMINATED TO THE
`
`PUBLIC.
`
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`

`Confidenual
`
`14.
`
`PATENT CERTIFICATION
`
`Allergan. lnc
`Brunorudine Tartrate C.5'1- Opht.biLlauc Soluuon
`Ongma.l hling For NDA Z0-613
`Secuon 14
`
`Because the only patent related to brimonidine for use in ophthalmic products has expired. no
`patent certifications will be made at this time. A copy of U.S. Patent No. 3.890,319, which
`covered the active compound brimonidine in Brimonidine Ophthalmic products and expired on
`17 June 1992, is provided in this NDA under Section 13, Patent Information.
`
`Page 8 of 286
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`

`

`PEDIATRIC PAGE
`
`IC~e lor II origNIIIJIIficalians n1 d elfoacy ~I
`
`Applicant
`
`Supplement # ~N~~~/4-'-'-- Circle one: SE1 SE2 SE3 SE4 SES SE6
`NDA/PLA # ,{ z'j) ft ,;90 - <R I 3
`Hf'b ··;'2 """D Trade (generic) name/dosage form: tiJp ~ v f{l.(_f/.c;,oa,;.,Lr + ,¥.a.u
`J C1~4J!IH,'-- Sc.;/v~)Ci.~ :;l
`dl/.""'r"""'
`Therapeutic C l a s s - - - - - ' -= - - - - - - - - - - -
`lndication!sl previously approved --::--.IJ...:~~==-----:;-:-----------------­
`Pediatric labefing of approved indication(s) is adequate ~madequate __
`
`Ar.tion:
`~k·•·ik-
`
`AP@NA
`
`1.
`
`2.
`
`PEDIATRIC LABEUNG IS ADEQUATE. Appropriate infonnation has been submitted in this or previous
`appUcations and has been adequately summarized in the labeling to penni! satisfactory labeling for an pediatric
`subgroups. Further infonnati6n is not rEquired.
`
`PEDIATRIC STUDIES ARE NEEDED. Th~re is potential for use in cltadren. and further infonnati~n is required to
`permit adequate labefing for this use.
`
`a.
`
`b.
`
`c.
`
`A new dosing fonnation is needed, and appficant has agreed to provide the appropriate fonnulation.
`
`The applicant has cvmmitted to doing such studies as wat be required.
`(1) Studies are ongoing,
`(2) Protocols werA submitted and approved.
`(3) Protocols were submitted and are under review.
`(4) II 09 protocol has been submitted, explain the status of cftscussions on the back of this form.
`
`If the sponsor is not willing to do pediatric studies, attach copies ol FDA's written request that such
`studies be done and of the sponsor's written response to that request
`
`v-:(
`PEDIATRIC STUDIES ARE NOT NEEDED. The drug/biolugili product has ittle potential for use in chndren.
`Explain. _on the back of this form. why pediatric studies are not needed. ~ s. , .,J, ad? u • •
`· ~ "-<'~
`P"- ,_._,.-,~-r , ,, · /:"'d''"'".;..,.·'- -pd. ,·,._:Y.s
`EX?LAIN.
`If none of the above apply, explain, as necessary, on the back of this form.
`4.
`
`EXPLAIN, AS NECESSAR¥. ANY OF THE FOREGOING ITEMS Oi'HRE BACK Of THIS FORM.
`
`d Title (PM, CSD, MD, other)
`
`I
`
`Date
`
`I
`
`cc: Ori~LA II C}(! · v 1 1
`HfU..:..-,·:,-1?
`/Div File
`NDA/PLA Action Package
`HF0-510/GTroendle (plus, for COER APs and AEs, copy of action letter and labefing)
`
`NOTE: A new Pediatric Page must be completed at the time of eath action even though one was
`prepared at the time of the last action.
`5195
`
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`

`1-\LLERGAN
`
`DEBARRMENT CERIIEICATION
`
`REF: Bnmonidine Tartrate 0.2% Ophthalmic Solution - NDA 20-613.
`
`Under the provisions of Section 306(1c) of the Federal Food, Drug and Cosmetic Act. Allergan.
`Inc. bas made a diligent effon to insure that no individual. corporation. pannersbip or
`a.o;sociation debarred under Section 306(a) or 306(b) of the Act. as referenced above. bas
`provided any services in connection with this application. This effon included identifying all
`employees of Ailergan. Inc. connected with this application and requiring each of them to
`certify that be or she bas not been debarred. This effoct also included a requirement that all
`persons not employed by Allergan. Inc. who provided services in connection with this
`application certify to us that neither they nor any person employed by them bas been disbarred.
`Relying. in part. on these certifications to us. Allergan, Inc. certifies that it did not and will not
`use. in any capacity. the services of any individual, corporation. parmersbip or association
`debarred under Section 306(a) or 306(b) of the Federal Food. Drug and Cosmetic Act in
`connection with this New Drug Application.
`
`Vice President. Global Regulatory Affairs
`Allergan. Inc.
`
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`

`

`Medical Officer's Review NDA 20-613
`Original
`
`1
`
`NDA 20-613
`Original
`
`Sponsor:
`
`Submission date:
`Received date:
`Review date:
`
`9fl/95, 4/5/96, 6/12/96
`9/13/95, 4/8/96, 6/14/96
`7/3/96
`
`Allergan Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, California 91713-9534
`
`Drug name:
`
`Alphagan
`
`Pharmacologic Category:
`
`Alpha adrenergic receptor agonist
`
`Proposea Indication:
`
`For the reduction of elevated intraocular pressure in
`patients with open angle glaucomd and ocular
`hypertension.
`
`Dosage Forrr and
`Route of Administration:
`
`Topical ophthalmic solution.
`
`Submitted:
`
`This application consists of 209 volumes divided into
`15 sections. The clinical section consisted of
`volumes 1. 136-1.142. The sporJsor has identified 2
`Pi1ase Ill studies as pivotal trials: #A342-103-7831
`and #A342-104-7831
`
`Manufacturing Controls:
`
`See Chemist's Review.
`
`Pharmacology:
`
`See Pharmacology and Toxicology Review.
`
`Related Submissions:
`
`IND#
`
`NDA#
`
`Page 11 of 286
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`

`

`Clinical Studies Conducted In Support of Brimonidine
`for the Reduction of Elevated lOP
`
`2
`
`Phase
`
`tudy
`Description
`
`Clinical
`Pharmacokinetics
`
`Safety and
`Comfon/
`Dose-titration
`
`Efficacy and
`Safety Dose
`Response
`
`A342-104-7831
`
`Page 12 of 286
`
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`

`

`Sru~, No.
`
`lnvestiaator
`
`Design
`
`Study
`
`Treatment
`
`Dose
`
`Duration
`
`Subjec.;" I ~ocY•e;r~c "'
`
`(Min-Max)
`
`Sex
`(MIF)
`
`Race•
`(B/W;Q)
`
`Sn.dy Conclusion
`
`3
`
`EH!y Dose-Tolerance Studies
`
`~~~4<-IU I· 7! UiboVIIZ
`29
`
`!::f<sted ~g~~
`Tnrauon
`vehicle
`
`~:'•.£·101·10 !Repass
`31
`
`~~:~~~ ~.~~~
`vehicle
`
`I'Jne eye
`Titrated
`0.02" qd
`() 02" bid
`0.~8" qd
`0.<)8" bid
`
`une eye
`bid
`
`4 aays
`
`44
`
`(lj8°~)
`
`jj/11
`
`41 J~/1
`
`4 aays
`
`)U
`
`o'r;'2)
`
`JM/11
`
`U/4//j
`
`~~42·1U8-!IU !Repass
`42
`
`~ .. ~_ed_ ~~t~le
`Par ailed
`
`IJDe eye
`bid
`
`4 oays
`
`40
`
`((9~)
`
`j j / I J
`
`U/40/0
`
`.
`
`!'l4<·111•01 1Ker.ss
`77
`
`~~!~1: ~~t~~e
`
`:IJDe eye
`bid
`
`4 oays
`
`40
`
`'
`
`(1';:67)
`
`<YII/
`
`U/4~14
`
`Brimonidine, at concentrations of
`0.02" and 0.08", is safe and
`comfonab\t.
`
`I
`
`ttnmon~dtne, at concentrauons of
`0.08" and 0.2'11\, is safe •nd
`'
`In addilion,
`comfortable.
`I
`brimonidine is more efficacious in ,
`lowering intraocular pressure than
`is vehide in normal subjects.
`There is no evidence from this
`sru~ 10 conclude thar brimonidine
`0.0 'II\ and 0.2'11\ differ from each
`other in etrJCacy .
`
`U.!unom<:une, at a concentration ot
`0.5'11\, is safe and comfortable.
`Si&nificanlly 1reater incidences of
`conjunctival blanchin& and
`subjective rr.rru of dry eye were
`reported wi use of brimonicline
`0.5'11\ dian vehicle. In addition,
`brimonidine is more efficacious in
`lowerin' intnocular rressure than
`is vehiCle in norma subjects.
`
`l!'unonld_me, 11 1 concenrnoon or
`0.35'11\, is safe and comfortable.
`Signifltllllly creater incidences of
`conjunctival bllnchinl WIS
`rersrted with u~ or brimonidine
`0. '" !han vehicle. In 1ddition,
`brimonidine is more eftk.acious in
`lowering intraocular pressure than
`is vehicle in normal subjects.
`
`Page 13 of 286
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`

`

`Study No.
`
`Investigator
`
`Design
`
`Study
`
`Treatment
`
`Dose
`
`Duration
`
`SubjeciSu• I ••••y.;,~· "'
`
`I (Min-Max)
`
`Sex
`(MIF)
`
`Race•
`(BIW/0)
`
`Study Conclusions
`
`4
`
`Shoo-I•!I!l ~tud!U o( Il!!:ra~utic ResJ!Qnse
`
`~~~1-109-78 Repasa
`29
`
`~a·~ ..... ~.~~~
`Para lied
`vehicle
`
`l"'a
`
`J aays
`
`u
`
`(3~'./9)
`
`""
`
`UIIJIU
`
`HJ!!!lO~KJ_me, at concentntJORS"'T"'
`O.Q2" and 0.08". is sate and
`comfortable. In addition, the
`resuiiS nf this stu~ sugr,siS that
`brimonidine 0.08
`is e IClcious
`for the treatment or elevated
`inlrllocular prusure. II must be
`kept in mind, however, that the
`
`very low. therefore. no u:n
`onclusions can be drawn from this
`study.
`
`1~1-11().7!
`
`ChorJiD
`Epstein
`Lewis
`
`:r
`
`Zimmerman
`Van Buskirk
`
`Para lied
`
`~·~-·d. ~·~;
`f>.os"
`vehicle
`
`I"KI
`
`~" aays
`
`)I.HliJ.U
`
`""'Yl
`
`'""
`
`.
`
`demonstrate that rwice-daily
`administered 0.08", 0.2". and
`O.S" brimonidine are lllllistically
`and cli~al~trcanr:;; more
`efficacJOus
`r1moru me
`vehicle in lowerins elevated
`intraocular l?ressure I 2 hours
`~st-instillanoo. Brimonidine
`
`2" and o.s" demonstrated a
`
`significantly greater peak ocular
`hYJ>Otensive effect than
`bnmonidine 0.08" or vehicle.
`
`slllt!Siical power of this :::1 wu
`.... ~, .. , 1 ~ nc restuts 01. uus ~!'>,'.
`
`Page 14 of 286
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`

`Study No
`
`lnvesti&ator
`
`-Design
`
`Study
`
`Treatment
`
`Dose
`
`Duration
`
`l"U~ocr OJ
`Subj<ct.s
`
`M . . n "gem
`Years
`(Min-Mu)
`
`Sex
`(MIF)
`
`Race•
`(B/W/0)
`
`Study Conclusions
`
`.>
`
`Stwn-I'rm ~9!dg Q( ibe[l~utK: Bes~n~ (~onlinued}
`
`jAJ4l-l D- 10 KObUI
`Nordlund
`31
`Pu<juale
`Rudikoff
`Ordman
`
`Maskea ~2s%
`~2't
`Crossover
`vehicle
`
`tweet
`
`5 weeks
`
`lb
`
`cit"),O)
`
`l4/U
`
`IO<>'V
`
`n uriS acut~_;oosmr, sruay m
`normal healtl>y vo unteers, no
`effects on ;mlmonary fun<:tion
`were observed with brjmonidine
`0. 2" • llctaxolol susrnsion
`0.25", timolol 0.5. or vehicle.
`Brimonidine 0.2", betaxo.ol
`su~nsion 0.25"' ond vehicle
`ha. no effect on exercise-induced
`tachycardia Mlereas timolol was
`associated w;th a statistically
`significant suppre!<ion of both
`exercise and recovery bean rate.
`The cardiovascular effects of
`brimonidine UP?n exercise were
`limited 10 a shght suppression of
`the systolic blood presrure during
`the recovery period.
`
`jA34l-l HHIU ll<ePUS
`42
`Walten
`Saraenr
`
`~~~f~~ ~~~~~.
`
`I""'
`
`• a•ys
`
`JU>
`
`-
`
`.. _, _,._.
`
`jU/j/
`
`1AJ4l-IIY-/O l~aiten
`31
`Bera
`
`Manea 1"-~,.
`Para lied
`
`l"ra vs. ua
`
`r< weeu
`
`lUI
`
`d~7J)
`
`401>>
`
`,., . .,.
`
`,,,. 1.~ oe re$\JIIS o.r _uus •"!._ay susgest
`that brimonidine 0. S"
`
`administered l'lll'ice-<laitr in either
`a regular-tip or micoo-bp is
`e(Jfall~flicacious in reducing
`I P.
`re were no differences
`'lll'ith regard to safety between the
`two drop sizes.
`1;..;':"~\'1';w~~ ."'ff~;~~ in the
`lowerinft of elevated lOP and
`was we -tolerated in subjects
`'lll'ith open-angle ~laucoma indlor
`ocular hypertensiOn.
`
`l
`
`Dosina of brimonidine 0.2 ~ three
`times per day otren oo clinically
`signifant advantage over rwtce
`per day dosing.
`
`Page 15 of 286
`
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`

`

`SrudteJ of Pbumf!CQib:namic f!:o~nte~
`
`~_,!42-10~-~0 p·lach
`42
`
`~~ IV'"
`
`stet
`
`1 aay
`
`•
`
`(22':2°4)
`
`.,v
`
`uu"
`
`1;14l-ll}()-/~ 'I'IOtnli
`
`Open
`
`~-'"'
`~a
`
`1010 .o:oung!
`qd (elderly)
`
`tv aay
`
`I days
`
`I
`
`9
`
`(23~~9)
`70
`(65-73)
`
`,,.
`3/6
`
`UID"
`
`0/9/0
`
`-
`
`6
`
`I
`
`1reu 1eve1S m. onmo~~ame_ m
`~lasma were detected Within four
`ours post-instillation of
`brimonidine 0.5~. D<lecuble
`levels of brimonidlne ranged from
`3.59 pg/roL to 265.00 pg/mL. No
`brimonH:iine was detectable in
`plasma al 24 hours
`posl-instillation. (The assay
`method emploJ.ed has the
`sensitivity 10 erect brimonidine in
`pl.,ma to the lower limit of 2.00
`pg/roL).
`1 ~ ne re"';'!,ts s~_a:a mat ocutar
`doses of 0.2 'I brimonidine
`tartrate to elderly aod you':f.
`subjecu were well tolerate .
`The systemic absorption was iow
`but detectable afler single aod
`I
`mul!iple ocular dosi~. The
`r:1ean Cmax wu 0.0 85 nJ.'mL
`after 10 dabs of repeated osing. 1
`S~;•temic I SO't>!ion and
`e imination of rimonidine in
`elderly subjects was comparable
`to that of young adults.
`Rdnated c~· 1 lar administration
`di Mt result il, si~nificant
`changes in brimomdine PK
`parameters, and there was
`minimal systemk accumulation
`following multiple dosing.
`
`i
`
`I
`
`j~_34l-ll0-IIO 11-lach
`42
`
`Masted
`
`Crossover
`
`~:~~"'o.5~
`vehicle
`
`qa
`
`t aay
`
`-'"·
`(27 safery
`analysis)
`
`(2'(3~)
`
`,.,u
`
`UIU,.
`
`1~ ~e mean hme at "'?•en
`maximum concentrations of
`brimonidine were found in
`human plasma (fmax) occurred
`at approximately two hours
`c:;st-dosing (range from I. 7
`ours to 3.2 hours). The
`concentration of brimonidine in
`plasma declined with an apparent
`elimination half-life ranging from
`two to five hours.
`I
`
`I
`
`Page 16 of 286
`
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`

`

`s37u-~u..:-l IIDIOOSkl
`
`Masked UT"'
`
`Uni1atera1
`
`I"'"
`
`------
`• aays
`
`-~
`
`"
`
`-
`
`<!!,_ 7's)
`
`,,.
`
`-
`
`-
`
`---
`
`IDI>IU
`
`7 .
`
`1 1 n~ D~Jmom'!~ne-~IK\ucea
`reduction in lOP in humans is
`associated with 1 decreast' in
`aqueous flow and an increase in
`uveoscleraJ outflow. The
`decrease in lOP and aqueous
`flow in the contralateral control
`eye on day 8 compared 10
`baseline day su,~cgests a miiu
`cuntralateral e ect.
`
`Page 17 of 286
`
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`

`

`Controlled Clinical Studies:
`
`----
`
`istt!dy
`No.
`
`Investigator
`
`Study
`Design
`
`Treatment
`
`Dose
`
`Duration
`
`1 urup
`
`[DIU
`
`0.5% Timolol
`
`Parallel
`
`~- ~ ~~ 7<>
`Atlas
`7831 Barnebey
`Choplin
`Craven
`David/Kiemperer
`Gross
`Hersh
`~orwitz
`ones
`Katz
`Labarta
`Lamping
`LevY
`Perell
`Rotberg
`Schuman
`Siegel
`Silverstone
`Sloan
`Sturm
`Terry
`[ortora
`Wilensky
`Zimmerman
`
`Numocr l'f;ve:r~e
`of
`Subjects (Min. Max)
`
`~-~
`
`~"
`1(27.9- 83.9)
`
`'!" ..... ,
`Sex
`Non-
`(M/F) White)
`·-
`:226'
`
`~'+ 1/":JD
`
`a
`
`I
`
`i
`
`i
`
`Page 18 of 286
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`

`

`ControUed Cllnlcal Studies (continued)
`
`Study
`No.
`
`Investigator
`
`Study
`Design
`
`Treatment
`
`Dose
`
`Number Mean Age
`of
`in Years
`Duration Subjects (Min. Max)
`
`(White/
`Sex
`Non-
`(M/F1 White)
`
`9
`
`Double
`Masked
`Parallel
`
`0.2%
`0.5% Timolol
`
`I drop
`
`bid
`
`483
`
`246/
`62.7 Brim
`(28.5-86.4) 237
`61.4 Tim
`(32. 8-83. 0)
`
`404/79
`
`A342-1 Abelson
`04-
`Balazsi/K...sner
`7831 Beehler
`Blaydes
`Brooks
`Cantor
`Cooke
`Crichton
`Dirks
`Fichman
`Foerster
`Gaasterland
`Goldberg
`Has~
`LcBanc
`Lewis
`M~ Mel
`Mikelberg
`Morrison
`Mundorf
`Murphy
`Spim
`Stamper
`Ticho
`Tingey
`Tr~ W tcrs
`
`
`
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`

`

`10
`
`APPLICANT'S RATIONALE FOR DOSE AND REGIMEN
`
`A three <lay dose-response study (S342-l 09-7829) was conducted that compared the safety and
`efficacy of brimonidme 0.02%, 0.08%, and vehicle in 13 subjects with glaucoma or ocular
`h~rtension (S342-109-7831). Subjects were treated twice-daily in both eyes. The results showed a
`Significant difference in mean lOP change from baseline only at one timepoint. At this visit, the
`0.08% group had a significantly greater decrease than the vehicle group.
`
`A one-month dose-response study (A342-ll0-7831) was conducted comparing the safety and efficacy
`of brimonidine tartrate 0.08%, 0.2%, 0.5%, and vehicle in !94 subjects with open-angle glaucoma or
`ocular hypertension (A342-116-7831; Derick et al., 1993). Subjects were treated twice-daily in both
`eyes. Results f:om this study indicated that all three brimonidirie concentrations lowered lOP
`Significantly more than vehicle at all follow-up visits (p<0.05). At days 14, 21, and 28, the 0.5%
`concentration lowered lOP to the same extent as the 0.2% concentration. The 0.5% concentration,
`however, was associated with a greater incidence of blurring of vision and foreign body sensation.
`Incidence of fatigue and/or drowsiness and dry mouth were also higher for this concentration than for
`either the 0.2% or the 0.08% concentrations. Based on the rc..111ts of the dose-response study,
`brimonidine 0.2% was selected for funher clinical development in the treaanent of open-angle
`glaucoma and ocular hypertension.
`
`Dosing of brunonidine 0.2% at rwice per day (b.i.d.) was compared to three times per day (t.i.d.) in
`a three-month study (A342-119· 7831) to ascertain if more frequent instillation would sigruficantly
`enhance overall clinical effectiveness (A342-ll9-7831). One-hundred one patients with glaucoma or
`ocular hypertension were randomly assigned to the b.i.d. or t.i.d. groups. The data demonstrated that
`t.i.d. dosmg did not enhance overall clinical effectiveness. At morning trough, lOP was reduced
`approximately 4 mm Hg for both dosing regimens. At the afternoon trough, t.i.d. dosing resulted in
`a significantly greater reduction in lOP at three hours (3 mm Hg greater with t.i.d. than b.i.d. dosing)
`and one hour ( 1.4 rnm Hg greater) before the evening dose. The value of this additional decrease is
`minimal, since a) lOP is generally lowest in the afternoon and evening (Henkind et al., 1973; David
`eta!, 1992), b) both regimens resu1tetl in afternoon trough lOPs of under 20 liliJl Hg, c) there was not
`an enhanced lOP reduction at the morning trough,.a."ld d) compliance will1ikely suffer with t.i.d.
`dosing (Kass et al , 1987). Brimonidine was safe whether dosed b.i.d. or t.i.d. The conclusion from
`this study was that while t.i.d. dosing was safe, it did not contribute to a clinically significant
`enhancement of efficacy.
`
`One small, additional study (A342-116-8042) was conducted to aso~rtain whether a smaller drop size
`(26 uL) of brimonidine would be as effective as the standard drop size (35 uL) while enhancing the
`safety profile (A342-110-7831). Sixty-seven patients with glaucoma or ocular hypertension were
`dosed b.i.d. for seven days. The results showed that the smaller drop size did not enhance the safety
`profile and therefore, the 35uL drop size was used iu all future studies.
`
`Reviewer's Comments: The applicants rationale for bid dosing is seriously flawed. The morning
`trough measured was taken in each group 9-12 hours after the n>~ning dose. Th~ ~quivaJence between
`groups is reflective of the equal arrwunts of time since the last dose in each group.
`The difference in the afternoon measurement d~monstrates 1M n~ed for an additional aft~moon dose.
`An occasional missed afternoon dose due to compliance issues is Still bmer than a routin~ly missed
`dose because it was not attempted.
`
`Page 20 of 286
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`

`11
`
`Study Design - Phase ill Studies
`
`In the two phase ill studies (A342-103-7831 and A342-104-7831), all patients were diagnosed with
`glaucoma and/or ocular h:yyenension. Patients were required to meet the following inclusion and
`exclusion criteria to panictpate in the study:
`
`Inclusion Criteria: Male or female volunteers, 21 years of age or older, with
`post-washout lOPs of 23 mm Hg or greater (but less than 35 mm Hg) in each eye at the Hour 0
`measurement, and corrected visual acuity of 20/80 (A342-104-7831) or 201100 (A342-103-7831)
`English units or tn.tter in each eye.
`
`Exclusion Criteria: Existence of any unccntrolled systemic disease:'; pregnancy,
`nursing, or child~ing potential (an adult female was considered of child~g potential uilless she
`was post-menopausal, had her uterus and/or both ovaries removed, or had a bilateral tubal ligation);
`contraindications to alplu:-adrenoceptor agonist therapy such as depression, cerebral or coronary
`insufficiency, Raynaud's phenomenon, onhostatic hypotension, or thromboangiitis obliterans;
`contraindications to beta-adrenoceptor antagonist therapy (such as chronic obstructive pulmonary
`disease, bronchial asthma, heart block more severe than firSt degree or uncontrolled congestive bean
`failure); abnormally lew or high heart rate or blood pressure for age; known hypersens;llvity to any
`of the ingredients in the study medication, or diagnostic agents used in the study; chronic treatment
`with any other topical or systemic alpha-adrenor.eptor agonist or alpha-adrenoceptor antagonist;
`alteration of exist:ng chronic therapy with agents which could have a substantial effect on lOP, a
`substantial effect on the ocular acttvity of alpha-adrenergic agonists, or substantially interact with
`alpha-agonists; and treatment with adrenergic-augmenting psychotropic drugs.
`
`Ophthalmic Exclusion Criteria: Corneal abnormalities that would preclude ac.:urate
`readings with an applanation tonometer, use of contact lenses during thf' study, any other actiw
`ocular disease, dry eye (with confirmation of a Schirmer strip test < 5 mm), Sjogren's syndrome or
`kerazoconjunctivitis sicca. required use of other ocular medications during the study, asymme~ of
`lOP > 5 mm Hg between eyes, visual field loss of 50% or greater or any visual field loss which in
`the opinion of the investigator was functionally significant, laser or other intraocular surgery within
`the past six months, and r.apping of the optic disc~ 0.8 in either eye.
`
`Study Design: Before study medications were dispensed, subjects provided written
`informed consent. At the prestudy visit (viSit 1), an ophthalmic examination COfl.sisting of assessments
`of intraocular pressure (lOP), visual acuity, biomicroscopy, ophthalmoSCOP.Y· pupil size, Schirmer
`tear test, and a visual field were performed to determine a subject's eligibility to panicipate in the
`study. Those subjects meeting the initial entry criteria were enrolled into the study and a medical and
`ophthalmic history was taken. For systemic safety evalu.-.tion, heart rate and blood pressure were
`measured. An ECG was optional at this visit. Blood samples were drawn to evaluate the subject's
`complete blood count (CBC) and blood chemistry.
`
`The washout period was four days to four weeks depending on the prestudy glaucoma medication that
`wa.> used. Following washout. all subjects returned for a. baseline examination (visit 2, day 0). If no
`washout period was required, visits I and 2 could occur on the same day. At this visit, baseline
`measurements vf lOP, visual acuity, pupil size, heart rate, and blood pressure were taken.
`Measurements of lOP were taken betWeen 7:30 and 9:30 am (corresponding to trough, 12 hours after
`treatment-hour 0 ) ~nd again between 9:30 and II :30 am (corresponding to peak, two hours after
`treatment). Biomicru~copy and a Schirmer tear test were performed. Subject comfon was also
`assessed. Subjects who qualified for entry were randomly assigned to one of the two treatment
`groups (brimonidine 0.2 \t or timolol 0.5% ). Subjects were instructed to instill the study medication
`at twelve hour intervals, between the hours of 7:30AM and 9:30AM and between 7:30PM and 9:30
`PM. for a duration of 12 mooths. Subjects were instructed not to use the morning medication on the
`day of a scheduled visit.
`
`Subjects rerurned for follow-up examinations at weeks I and 2, and months I, 2, 3, 6, 9, and 12. At
`these elUIII11Ilations, efficacy was assessed by evaluating changes from baseline in lOP, visual fields,
`and cup/disc ratio (month 6 and 12). Ocular safety was asseSsed by evaluating changes from baseline
`in visWII acuity. pupil size, biomicroscopy, a.1d ocular discomfon. A Schirmer tear test (month 6 and
`12) and an ophthalmoscopic euminauon (month 6 and 12) were also assessed for ocular safety.
`Systemic safety was assessed by evaluating changes from baseline in bean rate and blood pressure,
`systemic discomfon, and CBC and blood chemistry (months 6 and 12). Peak (two hours
`post-instillation) measurements of lOP were tai.::en at week I and 2, and at months I, 3, 6, and 12.
`Subject cornfon was also assessed at all follow-up visits.
`
`Page 21 of 286
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`

`

`Statistical Analysis: One year data from A342-103-7831 and six-month data from
`A342-J04-783J were analyz•.:d in each respective final report. In this integrated swnmary,
`meta-analysis was performej for !he combined six-month data from both studies. However, in some
`tables/graphs, Months 9 and 12 data from A342-J03-7831 were also included.
`
`Intraocular pressure was the key variable for both pivo!al studies. A p-value less !han or equal 10
`0.05 was considered statistically significant for the main effects and 0.10 for the treannent-by-study
`interaction effects.
`
`The followin
`
`12
`
`tagnos!S,
`
`two-way
`
`two-way
`
`me
`
`oscopy, ocu ar an
`wnucroscopy, op
`systemic discomfort, adverse events
`
`1-square test or
`
`;
`two-way
`significant changes
`
`two-way
`
`two-way
`
`two-way
`
`es
`
`;
`two-way
`baseline as a covariate
`
`covanance wt
`
`Two major analyses were performed on the two combined studies:
`
`(I)
`
`(2)
`
`Preferred Analysis. Subjects from the efficacy analyzable population were included in this
`analysis. The preferred analysis was the primary analysis for efficacy.
`
`Responder Analysis. Responders were defmed as subjc:-..-u included in the preferred analysis
`with an lOP reduction of at least 3 mm Hg or greater from baseline at two consecutive visits
`within the first month of treatmem (trough effect, Hour 0 measurement).
`
`Page 22 of 286
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`

`

`Study # 1
`Protocol # A342-103-7831
`
`Demographics
`
`(All S\.lbj ects)
`
`13
`
`Variable
`
`Age (Years)
`
`Sex
`
`Race
`
`N
`Mean
`SD
`Min
`Max
`
`<45
`45-65
`>65
`
`Male
`Female
`
`0.2t Brill
`
`0.5t Tim
`
`All
`
`P-value
`
`221
`62.6
`ll.2
`27.9
`83.9
`
`222
`62.5
`10.3
`34.4
`83.4
`
`443
`62.5
`10.7
`27.9
`83.9
`
`0. 969
`
`33( 7.4\-)
`17
`( 7.2t)
`16
`( 7. 7\)
`204 ( 46. Ot)
`100 (45. 2t) 104 (46.8t)
`104 (47.lt) 102 (45.9t) 206( 46.5t)
`
`100 (45.2t) 117 (52.7\) 217( 49.0t) 0.134
`lOS (47.3t)
`226( Sl.Ot)
`121 (54. Btl
`
`Caucasian
`Hispanic
`Black
`Asian
`Other [b)
`
`175 (79.2t) 172 (77.5t)
`16 ( 7 .2t I
`le ( 8.1\)
`25 (1l.3t)
`26 111.8\)
`( l . Bt)
`5
`( 2.3t)
`4
`0 ( 0. Ot)
`( 0.9\)
`2
`
`34 7 { 78.3t) 0.585
`34( 7. 7\)
`Sll ll.St)
`9( 2. Ot)
`2 ( 0.5t)
`
`Iris Color
`
`Blue
`Green
`Hazel
`Brown
`
`79 (35.7~)
`12 { 5. 4t)
`23 (10.4\)
`107 (48.;4t)
`
`79 (3S.6t)
`5
`( 2.3t)
`27 (12. 2t)
`111 (SO.Ot)
`
`158 ( 35. 7t) 0. 710
`17 I 3. stl
`SOl 11.3\-)
`2l.B( 49.2t)
`
`Diagnosis
`
`OAG
`OI!T
`OAG/OI!T [c)
`
`137 (62.0t) 138 (62.2t) 275( 62.lt) 0.933
`80 (36.0t)
`81 (36.7\)
`161 ( 36.3t)
`( l.Bt)
`I 1.4t)
`3
`4
`71 1. 6t)
`
`[b) Other: two Hawaiians
`[c) One eye with OAG and the fellow eye with OHT.
`
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`

`14
`
`Demographics
`
`(Preferr"d Analysis)
`
`Variable
`
`Age (Years)
`
`Sex
`
`Race
`
`N
`Mean
`SD
`Min
`Max
`
`<45
`45-65
`>65
`
`Male
`Female
`
`0.2\ Brm
`
`0.5\ Tim
`
`All
`
`P-value
`
`186
`62.7
`11.4
`27.9
`83.9
`
`0.713
`
`188
`62.2
`10.3
`34.5
`81.4
`
`374
`62.5
`10.9
`27.9
`83.9
`
`( 8.H)
`15
`81 (43.5\)
`90 (48.4\)
`
`28( 7.5\)
`( G . 9\)
`13
`90 (47.9\) 171( 45. 7t)
`85 (45 .2\) 175( 46. at)
`
`84 (45. 2\)
`102 (54.8\)
`
`187 ( 50.0\) 0.052
`103 (54.8\)
`85 (45. 2\) 187( 50.0\i
`
`Caucasian
`Hispanic
`Black
`Asian
`Other [b]
`
`150 (80.6\)
`( 7. 5\)
`14
`( 9. 7\)
`18
`( 2.2\)
`4
`( 0.0\)
`0
`
`145 (77. H)
`17
`( 9.0\)
`21 (11.2\)
`4
`( 2. H)
`( 0.5\)
`1
`
`295 ( 78. 9\)
`31( 8.3t)
`39( 10.4.\)
`8 ( 2.1\)
`1 ( o.n>
`
`0.456
`
`Iris Color
`
`Blue
`Green
`Hazel
`Brown
`
`69 (37.H)
`( 4. 3\)
`8
`20 (10.8\)
`89 (47.8\)
`
`68 (36.2\)
`( 2.7\)
`5
`20 (10.6\)
`95 (50.5\)
`
`137 ( 36 .6\) 0.648
`13 ( 3.5\)
`40 ( 10. 7t)
`184 ( 49.2\)
`
`Diagnosis
`
`OAG
`OHT
`OAG/OHT [c)
`
`115 (61.8\)
`68 (36 ."6\)
`( 1.6\)
`3
`
`118 (62.8\)
`66 (35. H)
`( 2. H)
`4
`
`233 ( 62.3t) 0.886
`134 ( 35.8t)
`7 ( 1. 9\)
`
`[b) Other: one Hawaiian
`(c) One eye with OAG and the fellow eye with OHT.
`
`Reviewer's Comment•: There was no significant differences between the two
`treatments groups in age, sex, race, iris color, diagnosis distribution,
`medical or ophthalmic history.
`
`Page 24 of 286
`
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`
`

`

`.nvestigators
`
`~a~m; and Addres~
`
`. Diane Albracht, MD
`2167S Redwood Rd
`Cuuo Valley, Cll. 94540
`
`Walter Atlas, MD
`Nalle Clinic
`1350 South Kings Dr
`Charloae, NC 2B207
`
`Howard Bamebey, MD
`90 I Boren St, Soite I 030
`Seallle, WA 98104
`
`Neil Choplin, MD
`Naval HospiLII of San Diego
`Dep<. of Ophthalmology, Code 69
`San Diego, CA 92134
`
`E. Randy Craven, MD
`Glaocoma Associates
`·so E. Harvard, Suite 205
`Jenver, CO 80210
`
`Roben David, MD
`llamar Klemperer, MD
`Ben-Gurion Univeniry of the Nege\·
`Sorou Medical Center
`Beer·Sheva 84101 Israel
`
`Ronald Gros.s. MD
`Baylor College of Medicine
`6SOI Fannin. CS29
`Houston, TX 77030
`
`Stanley Hersh, MD
`1201 W. MaiD